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Gerzen, O.P.; Votinova, V.O.; Potoskueva, I.K.; Tzybina, A.E.; Nikitina, L.V. Accumulation, Competition, and Toxicity of Divalent Cations. Encyclopedia. Available online: https://encyclopedia.pub/entry/46863 (accessed on 03 July 2024).
Gerzen OP, Votinova VO, Potoskueva IK, Tzybina AE, Nikitina LV. Accumulation, Competition, and Toxicity of Divalent Cations. Encyclopedia. Available at: https://encyclopedia.pub/entry/46863. Accessed July 03, 2024.
Gerzen, Oksana P., Veronika O. Votinova, Iulia K. Potoskueva, Alyona E. Tzybina, Larisa V. Nikitina. "Accumulation, Competition, and Toxicity of Divalent Cations" Encyclopedia, https://encyclopedia.pub/entry/46863 (accessed July 03, 2024).
Gerzen, O.P., Votinova, V.O., Potoskueva, I.K., Tzybina, A.E., & Nikitina, L.V. (2023, July 17). Accumulation, Competition, and Toxicity of Divalent Cations. In Encyclopedia. https://encyclopedia.pub/entry/46863
Gerzen, Oksana P., et al. "Accumulation, Competition, and Toxicity of Divalent Cations." Encyclopedia. Web. 17 July, 2023.
Accumulation, Competition, and Toxicity of Divalent Cations
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This entry is adapted from the peer-reviewed paper 10.3390/ijms241310579

The binding of calcium and magnesium ions to proteins is crucial for regulating heart contraction. However, other divalent cations, including xenobiotics, can accumulate in the myocardium and enter cardiomyocytes, where they can bind to proteins.

cardiotoxicity toxic ions divalent cations heart muscle

1. Accumulation in the Myocardium and Cardiotoxic Effect of Divalent Cations

Myocardium was found to accumulate various chemicals, such as aluminium [1][2][3][4], antimony [5], barium [1], cadmium [1][6][7][8][9][10][11][12][13][14][15][16], calcium [17][18][19], caesium [1], cobalt [5][8], copper [1][8][17][18][19][20][21][22], chromium [1][5][17][23], gold [5], iron [17][18][24], lead [1][8][9][12][25], magnesium [18][19], manganese [1][8][17][18][26], mercury [5][6], molybdenum [1][18], nickel [1][8][17][23][24][27][28], strontium [1][17], tin [1], and zinc [1][7][8][9][10][12][17][18][19][22]. Amongst them, there are elements with the primary oxidation state of +2.
The above-mentioned divalent cations can be divided into three groups [29][30][31]:
  • Essential ions for physiological processes (Ca2+, Cu2+, Fe2+, Mg2+, Zn2+, Mo2+).
  • Nonessential ions with no or low or unknown toxicity (Ba2+, Sr2+, Co2+, Ni2+).
  • Nonessential and highly toxic ions (Cd2+, Pb2+, Hg2+).
Some other less toxic mono-, di-, and trivalent cations also tend to accumulate in the myocardium and have been used as calcium analogues in various studies, e.g., La3+ and Tb3+ have been widely used as Ca2+ surrogates to examine metal binding properties and conformational changes of Troponin C [29][30][32].
Nevertheless, researchers focused on the nonessential toxic divalent cations from the 3rd group viz. Cd2+, Pb2+, and Hg2+, which are ubiquitous chemicals and considered to be important co-exposures [33]. Chronic exposure to cadmium [34][35], lead [36][37][38], and mercury [39] has been associated with multiple cardiovascular diseases. Cardiotoxicity after chronic and acute exposure was experimentally confirmed in the animal models for cadmium [6][40][41][42][43][44], lead [9][25][45][46][47], and mercury [6]. The direct cardiotoxic effect of cadmium [48][49][50][51], lead [30][52][53], and mercury [30][54][55] was confirmed at different levels of organization, including the whole heart, multicellular, cellular, and protein level.
It is worth noting that excess of some essential divalent cations from the 1st and 2nd groups could also be highly toxic. For example, Cu2+ could have mediated toxic effects through chronic exposure [21] and direct toxic effects [56][57][58] on the cardiovascular system. Ni2+ [59][60][61] and V2+ [59][61] exposure could also be connected with cardiovascular diseases (CVD). Co-exposure to Cu2+, Mo2+ and V2+ could be closely connected with CVD mortality [62]. Other essential cations like Ba2+, Mn2+, Co2+, Ni2+, and Zn2+ could have a direct effect on cardiac cells [51][63], especially on transport channels, whilst Ca2+, Mg2+, and Sr2+ appear to have less effect [63].
There have been informative reviews that broadly cover the topic of the effect of exposure to toxic metals on the cardiovascular system. For instance, there are reviews available for xenobiotic metals like lead [64][65], cadmium [64][65][66][67], mercury [39][64][65], and essential but toxic copper [65][68]. However, the direct effect of these ubiquitous chemicals on the cardiovascular system has not been extensively covered in reviews and is usually described in experimental articles. Furthermore, there are no comprehensive reviews and only limited information regarding the direct effect of these divalent cations on cardiac or skeletal muscle proteins.

2. Competition of Divalent Cations in the Body

Toxic cations such as cadmium, lead, and mercury can compete with other physiologically relevant divalent cations for entry into cells and in various biochemical reactions in the body. For example, cadmium absorption and accumulation may increase with zinc deficiency as cadmium can replace zinc in biochemical reactions [69][70][71][72][73]. Cadmium is also known to develop toxicity by competing with essential metal cations including calcium [32][74], iron, copper, and manganese for entry pathways [75]. Toxic cations can also deplete other important nutrients in the body, such as cadmium’s ability to deplete selenium, which is a crucial antioxidant and cofactor for various enzymes [76]. On the other hand, selenium is found to diminish cadmium cardiotoxicity [77]. Molecules specialized in the handling of alkaline earth (e.g., Mg2+, Ca2+) and transition metal ions (e.g., Zn2+, Cu2+, Fe2+) may be particularly sensitive to the presence of Cd2+ because they enclose cationic sites to which the toxic metal can bind [78].
Pb2+ can substitute calcium in calcium-binding proteins critical for heart function due to its similarity to Ca2+ [30][79][80][81]. Similarly, Pb2+ can replace other divalent metals such as zinc in zinc-finger proteins [82][83]. Lead can potentially lead to magnesium deficiency by inhibiting its absorption, which, in turn, may aggravate the negative effects of lead on the human body [84].
Both lead and mercury are powerful oxidizing agents in their +2 cationic state, with the ability to interfere significantly with processes that require specific divalent cations [30]. For example, mercury can interfere with Mg2+-binding sites because of their similar enthalpy energy dehydration values [30]. Interestingly, both toxic mercury and cadmium could have a competitive relationship in the accumulation in the myocardium [6].
Overall, competition between cations in the body is a vast topic that encompasses a range of divalent and trivalent ions that can compete for metal-binding structures in various tissues. For instance, Zn2+, Cu2+, Cd2+, and Hg2+ could compete for metal-binding sites of cardiac submitochondrial fragments [85]. Calcium can be replaced by strontium in various intracellular processes due to their high level of similarity [86]. Trivalent ions, e.g., Al3+ could also compete with Mn2+ and Mg2+ for binding sites due to their similarly small size [87][88][89].
In summary, understanding the competition between divalent and trivalent cations in the body is crucial for identifying potential strategies for preventing or treating cation-induced toxicity. Herewith, it is important to focus on their potential targets in the myocardium, as the known competition of two specific divalent cations in other tissues may be impossible in myocardium due to the absence of ways of entering for one or both cations in cardiac cells.

3. Entry Pathways for Divalent Cations into Cardiomyocytes

Various divalent cations interact with specific parts of the channels to affect their function [63]. Essential cations like calcium, magnesium, zinc, copper, etc. usually have their specific transporters or ion channels to enter cardiomyocytes [90]. For example, Mg2+ primarily enters cardiomyocytes through MgtE (SLC41A1) [91] and ACDP2 [92], and to a lesser extent through SLC41A2 [93], MMgT1, and MMgT2 [94].
Non-essential cations such as cadmium, lead, and mercury do not have specific ion channels or transport proteins on the cell membrane. Instead, they can utilize existing transport pathways to enter the cells [30][90]. For example, P1B-ATPases, which are transporters for cations via the membrane, are involved in the transport of Mn2+, Co2+, Cu2+, Ag+, Zn2+, Cd2+, Hg2+, and Pb2+, and may also play a role in Fe2+ and Ni2+ transport [95][96]. On the other hand, toxic metals like Pb, Cd, and Hg can enter tissues through multiple mechanisms due to ionic mimicry [97].
Cadmium has no specific ion channels or transport proteins on the cell membrane, and utilizes the transport pathways for calcium, zinc, iron, copper, and magnesium [50]. Cd2+ can enter cardiomyocytes through voltage-dependent Ca2+ channels [49][50][76], and inhibit or block the L-type Ca channel current in rabbit [98] and rat [99] ventricular myocytes. Detailed reviews devoted to cadmium entry through Ca2+ channels, transporters, receptors [75], and multiple sarcolemmal pathways, including Zn transporters [100], were published recently.
Lead ions can enter cardiomyocytes through various mechanisms, including Cav1.2 calcium channels [30], zinc transporters, anion exchangers, and non-voltage-dependent pathways [30]. Interestingly, currents through the Cav1.2 channels are smaller in the presence of Pb2+, but they last longer compared to those carried only by Ca2+ [30][53], similar to what has been described for inactivation by Ba2+ [101]. Moreover, Pb2+ can enter the cell through Trp channels with Ca2+-permeant pores that are known to be secondary entry pathways for divalent cations, in addition to other transport proteins like the Na+—Ca2+ exchanger, SOC channels, Zn2+ and other divalent metal transporters, pH-sensitive transporters, and aquaporin channels [30]. For details, see the review devoted to lead and mercury effects on voltage-gated calcium channel functioning [102].
Mercury ions can enter cells through various mechanisms, including ABC-type transporters, amino acid transporters, and organic anion transporters. Since Hg2+ has a large ionic radius, it is unlikely that it enters the cardiomyocytes through Cav1.2 channels and it is more likely that it just blocks them. Although mercury may not enter through Cav1.2 channels [30], it potentially can enter cardiomyocytes through several pathways, including calcium transporters. Additionally, mercury ions can also enter cells via transporters for other divalent cations such as Zn2+ and Cu2+. It is worth noting that inorganic mercury has a low lipophilicity and thus has a limited ability to cross cell membranes [103].
For other non-essential cations, it is also possible to enter the cells. For example, nickel can enter cells through divalent metal transporters and inhibit mitochondrial function, leading to oxidative stress and DNA damage [90]. Cobalt is a harmful cation which can enter cells through calcium channels and disrupt mitochondrial function, leading to oxidative stress and apoptosis; cobalt excess can also cause severe cardiomyopathy [104][105]. The cardiac ryanodine receptor provides a suitable pathway for the rapid transport of Zn2+ [106], and the sarcoplasmic reticulum in cardiac muscle is suggested to act as a dynamic storage for Zn2+ release and reuptake [106].
Non-essential and non-native essential cations can use multiple transport processes to enter various cells. Most of these transport pathways have been confirmed to allow various cations to enter cardiomyocytes. For example, L-type calcium channels are a suitable entryway for Sr2+ [86], Fe2+ [107], Ni2+ [90], Cd2+ [108], and Pb2+ [30]; T-type calcium channels are suitable for Fe2+ [107] and Cd2+ [108]; store-operated channels (SOC) for Pb2+ [30]; transient receptor potential (TRP) channels for Fe2+ [107] and Pb2+ [30]; Piezo type mechanosensitive ion channel component 1 (Piezo1) for Hg2+ [109]; sodium-calcium exchanger (NCX) for Sr2+ [86] and Pb2+ [30]. Aquaporins could be used by Pb2+ [30]; magnesium transporters E (MgtE) by Mn2+ [91]; zinc-regulated, iron-regulated transporter-like proteins (ZIP) by Mn2+ [110], Fe2+ [107], and Cd2+ [110]; divalent metal transporter 1 (DMT1) by Mn2+ [111], Zn2+ [111], Cu2+ [112], Cd2+ [113], Pb2+ [30], and Hg2+ [114].
Once inside the cell, divalent cations such as cadmium [49][97][115][116], lead [115][116], and mercury [39][54][97] ions can bind efficiently to sulfhydryl groups (-SH) of proteins. This interaction of cations with thiol and other groups is a crucial factor in understanding the toxic effects of these cations on the body. These toxic cations can target important sites such as the calcium- and magnesium-binding sites of troponin C, the ventricular and atrial myosin regulatory light chains, and the ATP-binding pocket of myosin, leading to disruptions in cellular processes and potentially harmful cardiac effects.

4. Toxic Effects of Different Concentrations of Divalent Cations in Cells

Numerous studies have confirmed the ability of heart tissue to accumulate various divalent cations. However, the fraction of accumulation of cations specifically in cardiomyocytes remains unclear, while the heart tissue is composed of different cell types, including cardiomyocytes, cardiac fibroblasts, smooth muscle cells, endothelial cells, etc. [117]. The range of concentrations of these cations in cardiomyocytes are unknown for most cations, and therefore the evaluation of the potential toxic effect connected with their concentrations is difficult.
It could be proposed that highly toxic xenobiotic cations such as Pb2+, Cd2+, and Hg2+ could have an adverse effect on the heart at any concentration within cardiomyocytes. For example, the addition of Pb up to 100 μM has been shown to have negative cardioinotropic effects on cardiomyocytes [53]. Similarly, the addition of 1 mM of Cd inhibited the time-dependent hyperpolarization-activated inward current on pulmonary vein and left atrial cardiomyocytes [118]. Heightened accumulation of mercury in the myocardium has been observed in idiopathic dilated cardiomyopathy (22-fold) and secondary forms of cardiac dysfunction (3-fold) patients [5].
While free Cu is absent inside cells [119], some essential divalent cations have a certain concentration in normal conditions. For example, intracellular rest Ca2+ is ~0.0001 mM/L and extracellular rest ~1.2 mM/L [120]. In toxic conditions, such as malignant hyperthermia, excessive calcium release from the sarcoplasmic reticulum leads to disturbances in intracellular Ca2+ homeostasis, uncontrolled skeletal muscle hypermetabolism, and arrhythmias [121][122]. The cytosolic free magnesium ion concentration is 0.85 ± 0.1 mM, but it can significantly increase to a level of 2.1 ± 0.4 mM under ischemia [123]. Another study has confirmed an increase in free intracellular Mg2+ concentrations under ischemia [124]. However, in the myocardial tissue of men with sudden death from myocardial infarction, the Mg2+ concentration is decreased [125].
To summarize, further research is needed to better understand the concentration range of various cations in cardiomyocytes, a topic which is still largely unknown, making it challenging to assess their potential toxic effects.

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Oksana P. Gerzen
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Iulia K. Potoskueva
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Alyona E. Tzybina
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Larisa V. Nikitina
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